Patients with progressive metastatic papillary thyroid cancer (PTC) have a poor prognosis. Despite advances in developing new therapies complete responses have been elusive and non-durable responses are the best reported outcomes. The presence of gross local invasion and distant metastases are two predictors of death from PTC. We have focused on defining key regulators of these features in an effort to identify novel targets to improve treatment. We identified that the p21 activated kinase (PAK) signaling is activated in the invasive fronts of aggressive PTCs and determined that it regulated human thyroid cancer cell motility and proliferation in vitro. We clarified that PAK1 is the primary isoform responsible for this effect. Because of the association between BRAF activation and tumor aggressiveness we analyzed the relationship between these two signaling molecules. We demonstrated that PAK activity was highly regulated by BRAF and that BRAF knock down inhibited PAK activity. Moreover, this effect was independent of MEK. We subsequently identified that PAK physically interacts with BRAF both overexpression and endogenous systems. We have shown in vivo that acute activation of BRAF V600E in the thyroid is associated with increased levels of phosphorylated PAK. Finally, we have demonstrated that aggressive PTCs that have metastasized have high levels activated PAK. These data point to PAK being a critical downstream target of BRAF which plays an important functional role in PTC progression for tumors with RAS/RAF/ERK pathway activation. Finally, we also have designed, developed, and tested several novel compounds that inhibit PAK and several other kinases reducing cell motility and viability in vitro. The hypotheses of this project is that PAK is a previously unrecognized critical signaling node downstream of BRAF involved in thyroid cancer tumongenesis and progression in vivo; that the mechanism ofthe interaction can be elucidated, and that the novel inhibitors we have developed will be active and tolerated in vivo in preclinical models.